DIABETIC NEPHROPATHY DIABETIC NEPHROPATHY

SUMMARY

Recommendations for Screening, Monitoring and Management of

Diabetic Renal Disease
Stage Definition Screening/Monitoring Management Grade
Stage 1/2 • Normal renal • Annual • Optimise A
Normoalbuminuria function urine protein glycaemic control
• Urine albumin dipstick • Treat A
concentration • Recheck if hypertensionn
< 20 mg/l positive (target BP <
• If negative test for 130/80) Statement of Intent
microalbuminuria
These guidelines are meant to be a guide for clinical practice, based on the
Stage 3 • Normal renal • Recheck urine for • Optimise A
Microalbuminuria function microalbuminuria glycaemic control best available evidence at the time of development. Adherence to these
• Dipstick negative 2 – 4 times per • Treat hypertension A guidelines may not necessarily ensure the best outcome in every case.
• Urine albumin year (target BP<130/80) Every health care provider is responsible for the management of his/her
concentration • Use ACEI/ARB A
20 – 200 mg/l for hypertension unique patient based on the clinical picture presented by the patient and
• AER 30 – 300 and/or the management options available locally.
mg/24h microalbuminuria
reduction Review of the Guidelines
• Avoid excessive C
dietary protein
and salt intake These guidelines were issued in July 2004 and will be reviewed in July
• Treat B
hyperlipidaemia
2006 or sooner if new evidence becomes available.
Stage 4 • Serum creatinine • Quantitate • Target BP B
Overt proteinuria normal or raised proteinuria 2 – 4 < 125/75 if
(Macroalbuminuria) • Dipstick positive times per year proteinuria
• Urine albumin • Renal profile > 1 g/day
concentration 2 – 4 times per • Use ACEI/ARB A
CPG Secretariat
> 200 mg/l year for hypertension c/o Health Technology Assessment Unit
• AER > 300 and/or proteinuria Medical Development Division
mg/24 h reduction
• Restrict protein B
Ministry of Health Malaysia
• Restrict salt B 21st Floor, Bangunan PERKIM
• Treat B Jalan Ipoh
hyperlipidaemia 51200 Kuala Lumpur
• Consider referral C
to a nephrologist
Stage 5 • Serum creatinine • As dictated by • Protect access C Available on the following websites :
End stage kidney > 500 µmol/L individual sites http://www.moh.gov.my
failure circumstances • Dialysis /
transplant http://www.acadmed.org.my
http://www.msn.org.my
AER = Albumin excretion rate, BP = blood pressure
Adapted from SIGN Guidelines(1)
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 DIABETIC NEPHROPATHY
DIABETIC NEPHROPATHY
PREFACE MEMBERS OF THE PANEL
Diabetes mellitus is a major cause of end stage renal disease (ESRD)
worldwide. In Malaysia the Dialysis and Transplant Registry 2002 Chairperson : Dr. Rozina Ghazalli
reported that diabetic nephropathy was the predominant cause of ESRD Consultant Nephrologist
accounting for 47% of new cases.(2) This places an enormous burden on
clinical, public health and economic resources as such patients often have Penang Hospital
multiple co-morbid conditions such as coronary artery and peripheral
vascular disease. Co-chairperson : Dr. Ong Loke Meng
Consultant Nephrologist
Thus the Malaysian Society of Nephrology council deemed it appropriate Penang Hospital
that a Clinical Practice Guideline on Diabetic Nephropathy be drawn up
to guide healthcare professionals, with the major objectives being Committee Members: (in alphabetical order)
screening for diabetic nephropathy and instituting measures to prevent or
retard its progression. Dr. Adlina bt. Bakar Dr. Koay Hean Chong
Family Physician Consultant Nephrologist
Butterworth Health Clinic Lam Wah Ee Hospital
This task was given to the Penang nephrologists as it dawned on the
council that the small island had a nephrologist in every corner! Apart Penang Penang
from nephrologists, the panel included an endocrinologist, a family
physician, an outpatient general practitioner, a cardiologist, and a Professor Amir S. Khir Dr. Ong Hean Teik
physician with interest in diabetes mellitus. The committee has attempted Consultant Endocrinologist Consultant Cardiologist and
to combine evidence based medicine with the practical strategies available & Professor of Medicine Physician
locally to formulate these recommendations. Penang Medical College H. T. Ong Heart Clinic Penang

These fourteen recommendations are intended to assist primary health Dr. Ang Hock Aun Dr. Punithavathi Narayanan
care doctors who manage diabetic patients in their day-to-day practice to Consultant Physician Head & Senior Medical Officer
intervene early and effectively so that the onset and the course of diabetic
nephropathy can be ameliorated. Seberang Jaya Hospital Outpatients Department
Penang Penang Hospital
I would like to take this opportunity to thank the panel members for their
hard work and commitment in preparing the guidelines. I would also like Dr. Chen Tse Peng Dr. Tan Chor Seong
to thank the secretariat for services rendered, all those who contributed to Consultant Nephrologist & Consultant Nephrologist &
the final draft presentation and finally to the Malaysian Society of Physician Physician
Nephrology council for their infinite patience in waiting for the Gleneagles Medical Centre Loh Guan Lye Specialist Centre
appearance of this guideline! Penang Penang

Dr. Foo Siu Mei

Clinical Specialist in Nephrology
Dr. Rozina Ghazalli Department of Medicine
(Chairperson) Penang Hospital
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 DIABETIC NEPHROPATHY DIABETIC NEPHROPATHY

DEVELOPMENT OF THE GUIDELINE

Table of Contents Page
• Relevant key words and terms were determined by the committee
Summary i
members. These were used to generate MEDLINE searches for
Statement of Intent ii scientific literature in the English language focusing on peer reviewed
Preface iii articles. The articles were retrieved for systematic review using a
Members of the Panel iv check list to assess the validity of the studies.
Table of Contents v • A draft of the guideline was formulated based on the systematic
Development of the Guideline 1 review of the literature including existing guidelines. Some
Introduction 2 recommendations were modified taking into consideration local issues
Diagnosis of Diabetic Nephropathy 2 such as costs and available resources. The rationale for the
modification was provided.
Natural History of Diabetic Nephropathy 3
Prevention of Diabetic Nephropathy 5 • The draft was subjected to peer review in stages. It was distributed to
Screening for Microalbuminuria and Overt Proteinuria 6 general practitioners, physicians, endocrinologists, nephrologists and
Algorithm : Screening for Proteinuria 8 Malaysian Society of Nephrology members and amended following
their comments. A discussion of the recommendations was then made
Management of Diabetic Nephropathy 9 at the annual seminar of the Malaysian Society of Nephrology in May
- Glycaemic control 9 2003 followed by an open forum for doctors in Penang.
- Blood pressure control 10
- Microalbuminuria 11 • This guideline is structured for ease of reference. Each guideline is
tabulated, numbered and titled. The evidence and rationale for the
- Overt proteinuria 12 recommendation is provided to enable the reader to make an informed
- Smoking 14 decision appropriate to the individual patient.
- Lipids 14
- Diet 16 • This guideline complements the existing guideline on “Care of the
Diabetic Patient (The Malaysian Consensus practice guideline :
- Referral 17 Second edition July 1999)”. The focus of this guideline is on the
Appendix 1 (Factors affecting urinary albumin excretion) 18 prevention, screening and management of diabetic nephropathy.
Appendix 2 (Methods of urine collection) 19
• Recommendations have been graded based on levels of evidence using
Appendix 3 (Methods of measurement of microalbuminuria) 21
the following system: -
Appendix 4 (Dosage of hypoglycaemic agents in renal failure) 22
Appendix 5 (Dosage of ACEIs and ARBs commonly used) 24
Appendix 6 (Estimation of renal function) 25 GRADE A Based on evidence from one or more randomised clinical
References 26 trials and/or meta-analyses.
GRADE B Based on evidence from high quality clinical trials but no
Glossary of Terms 38 randomised clinical trial data available.
Disclosure Statement 38 GRADE C Based on expert committee reports and/or clinical
Acknowledgements 38 experience of respected authorities but lacking in directly
applicable studies of good quality.
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 DIABETIC NEPHROPATHY DIABETIC NEPHROPATHY

INTRODUCTION • Concomitant renal artery stenosis should be suspected :-

• In recent years there has been an increase in the prevalence of diabetes
worldwide. In Malaysia the prevalence of diabetes has increased from
6.3% in 1986 to 8.3% in 1996.(3)
• With improvement in the survival of patients with diabetes,
nephropathy has now emerged as a major health problem.
• Nephropathy develops in about 20-40% of diabetics. Known risk
factors for the development of diabetic nephropathy include genetic
predisposition, poor glycaemic control, hypertension and smoking.
• Prevention, early detection and aggressive intervention are needed to
retard the progression of diabetic nephropathy to end stage renal
failure.
• Cardiovascular disease is the commonest cause of death in patients
with diabetic nephropathy. Thus it is necessary to address the
associated risk factors for this condition.
- when rapid deterioration of renal function occurs with angiotensin-
converting enzyme inhibitors (ACEIs) or angiotensin receptor
blockers (ARBs)
- in the presence of severe peripheral vascular disease, renal bruits,
severe uncontrolled hypertension or unequal sized kidneys
NATURAL HISTORY OF DIABETIC NEPHROPATHY
• Diabetic nephropathy is a spectrum of progressive renal lesions
secondary to diabetes mellitus ranging from renal hyperfiltration to
end stage kidney disease.
• The earliest clinical evidence of nephropathy is the presence of
microalbuminuria (Table 1). It occurs in 30% of type 1 diabetics, 5 to
15 years after diagnosis but may be present at diagnosis in type 2
diabetics as the time of onset of type 2 diabetes is often unknown.
• Microalbuminuria progresses to overt proteinuria over the next 7 to 10
years (Figure 1).

DIAGNOSIS OF DIABETIC NEPHROPATHY • Once overt proteinuria develops, renal function progressively declines
and end stage renal failure is reached after about 10 years.
• The diagnosis of diabetic nephropathy is usually made clinically. Other
target organ involvement is often present. 90-95% of type 1 diabetics
and about 70% of type 2 diabetics with nephropathy will have
retinopathy as well. In the absence of retinopathy, non-diabetic renal
disease may need to be excluded.

• Non-diabetic renal disease should also be considered when :-

- significant haematuria or urinary red blood cell casts are present
- renal failure occurs in the absence of proteinuria
- there is evidence of other systemic disease e.g. systemic lupus
erythematosus, myeloma, viral hepatitis

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 DIABETIC NEPHROPATHY DIABETIC NEPHROPATHY

Table 1. Evolution of Diabetic Renal Disease PREVENTION OF DIABETIC NEPHROPATHY

Stage 1 • Glomerular hypertension and hyperfiltration
• One of the most important aspects in the management of diabetes
• Normal albuminuria: urinary albumin excretion rate (AER)
mellitus is to prevent macrovascular and microvascular complications
<20 µg/min
including diabetic nephropathy and cardiovascular disease.
• Raised GFR, normal serum creatinine
Stage 2 • “Silent phase” (structural changes on biopsy but no
• This may require a multidisciplinary team approach which includes
clinical manifestations)
general practitioners, physicians, endocrinologists, dietitians and
• Normoalbuminuria
trained diabetic nurses.
Stage 3 • Microalbuminuria: AER 20 – 200 µg/min
• Normal serum creatinine
• The focus of management should be on good glycaemic control which
• There may be increased blood pressure
includes patient education, lifestyle modification, diet, exercise,
Stage 4 • Overt “dipstick positive” proteinuria (macroalbuminuria) :
attainment of ideal body weight and frequent self-monitoring of blood
AER > 200 µg/min
glucose.
• Hypertension
• Serum creatinine may be normal
• The strongest evidence in the prevention of diabetic nephropathy and
• Increase in serum creatinine with progression of
other microvascular complications has been with tight glycaemic
nephropathy
control. The Diabetes Control and Complications Trial (DCCT) in type
Stage 5 • End stage renal failure
1 diabetics(5,6) and the United Kingdom Prospective Diabetes Study
• Requiring dialysis or transplant to maintain life
(UKPDS) in type 2 diabetics(7) have shown that intensive blood glucose
Adapted from SIGN Guidelines (1) control reduces the risk of developing nephropathy, retinopathy and
neuropathy.
Figure 1. Natural history of diabetic nephropathy(4)
• Strategies to prevent diabetic nephropathy also include monitoring and
Hyperfiltration
(functional changes) tight control of blood pressure.
Stage 1
Incipient Overt
nephropathy nephropathy ESRD
Stage 3 Stage 4 Stage 5

0 2 5 Time(yrs) 10-30 13-25 20-40

Onset of Onset of Rising Dialysis/

diabetes proteinuria creatinine Transplant

Silent phase
(structural changes)
Stage 2

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 DIABETIC NEPHROPATHY DIABETIC NEPHROPATHY

SCREENING FOR MICROALBUMINURIA AND Recommendation 2 : Method of screening for proteinuria

OVERT PROTEINURIA
Urine should be screened for proteinuria with conventional dipstick on
an early morning urine specimen*
• Microalbuminuria refers to the presence of a small amount of albumin
in the urine, which cannot be detected with the usual urine dipstick. Grade C
The definition depends on the method of urine collection (Table 2). * Other factors affecting urinary albumin excretion should be excluded when screening
for microalbuminuria and proteinuria (Appendix 1).
Table 2. Definition of abnormal urinary albumin excretion(1)
SPECIMEN COLLECTED Recommendation 3 : Screening for microalbuminuria
First voided morning (a) If urine dipstick for proteinuria is negative, screening for
specimen
microalbuminuria should be performed on an early morning urine
Urine specimen
Urine Albumin: (b) Urine dipstick for microalbuminuria is an acceptable screening test
Albumin Excretion 24 hr Timed Albumin Creatinine
(c) If microalbuminuria is detected, confirmation should be made with
collection collection concentration* ratio**
two further tests within a 3 to 6 month period (see Algorithm)
(mg/24h) (µg/min) (mg/l) (mg/mmol)
<3.5 women (d) If microalbuminuria is not detected, re-screening should be
Normoalbuminuria <30 <20 <20
<2.5 men performed annually
Microalbuminuria 30-300 20-200 20-200 3.5 to 35 Grade C
women
2.5 to 25
men • Timed urine collection is the gold standard for screening and
Overt proteinuria >300 >200 >200 >35 women quantification of urinary albumin excretion. However this is
>25 men expensive, impractical and collection is often incomplete. Refer to
* urine albumin of 200mg/l is equivalent to 300mg/l of protein
Appendix 2.
** 3.5 as lower limit in females because of lower creatinine excretion
• Urine dipstick testing for albumin concentration or albumin/creatinine
ratio are quick, convenient tests that can give rapid on-site results.
Recommendation 1 : Screening for proteinuria Both tests have reasonable sensitivity and specificity(8).
Screening for proteinuria should be performed yearly in the following
patients*: • Early morning urine should be used to minimise fluctuations in urinary
(a) Type 1 diabetes mellitus: 5 years after diagnosis of diabetes, or concentration and changes in AER related to posture and physical
earlier in the presence of other cardiovascular risk factors activity. Currently available methods for screening of
(b) Type 2 diabetes mellitus: at the time of diagnosis of diabetes microalbuminuria are listed in Appendix 3.
Grade C
* Other factors affecting urinary albumin excretion should be excluded when screening
for microalbuminuria and proteinuria (Appendix 1).
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 DIABETIC NEPHROPATHY DIABETIC NEPHROPATHY

Algorithm : Screening for Proteinuria

MANAGEMENT OF DIABETIC NEPHROPATHY
Urine dipstick for protein
• The development of diabetic nephropathy has a devastating impact on
(a) Type 1 : 5 years after diagnosis
or earlier in the presence of other morbidity and mortality of patients with diabetes mellitus.
cardiovascular risk factors Microalbuminuria is a powerful and independent predictor of
(b) Type 2 : at the time of diagnosis cardiovascular death.(9,10)

• Therapeutic intervention should include strategies to prevent or retard

NEGATIVE POSITIVE Overt nephropathy the progression of diabetic renal disease as well as to reduce
(urine protein >300mg/l) • Quantify excretion cardiovascular complications.
on 2 separate occasions rate e.g. 24-hr urine
(exclude other causes e.g. protein • The management of these patients includes good glycaemic control,
UTI, CCF etc.) • Exclude other tight control of blood pressure, reduction of proteinuria with ACEIs or
nephropathies ARBs, cessation of smoking, lipid control and salt and protein
Screen for POSITIVE restriction.
microalbuminuria * Optimise
on early morning glycaemic control Glycaemic Control
spot urine * Strict BP control
* ACEI/ARB Recommendation 4 : Glycaemic control
* Lifestyle Glycaemic control should be optimised, with FBS ≤ 6 mmol/l and/or
NEGATIVE Retest twice in 3 –6 modification HbA1c ≤ 7%
months (exclude other * Stop smoking Grade A
causes e.g. UTI, * Treat FBS = fasting blood glucose, HbA1c = glycosylated haemoglobin
CCF etc.) hyperlipidaemia
* Avoid excessive • In type 1 diabetes mellitus, intensive treatment usually with multiple
salt intake insulin injections, coupled with self-management education and self
Yearly test * If 2 of 3 tests are * Avoid excessive
for
monitoring of blood glucose can achieve near ideal glucose and
positive, diagnosis of protein intake HbA1c goals. The risk of getting microalbuminuria and albuminuria is
microalbuminuria microalbuminuria is * Monitor renal reduced with intensive treatment. (5)
established function
* 3-6 monthly follow-up * Monitor for other • Maintaining the HbA1c target long term can sustain the benefits.(6)
of microalbuminuria diabetic end-organ
damage • In type 2 diabetes, intensive blood glucose control can reduce the risk
of microvascular endpoints including albuminuria irrespective of the
drugs used,(7) except in overweight diabetics where metformin was
Adapted from Practice Guidelines for Diabetes Mellitus type 2. The Malaysian consensus : shown to have a significantly greater effect on any diabetic related
Second Edition (July 1999)
endpoints.(11)
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 DIABETIC NEPHROPATHY
• Any reduction of HbA1c can reduce the risk of diabetic
complications.(12)
• In the presence of renal failure the dose of hypoglycaemic agents
should be adjusted to avoid hypoglycaemia. Refer to Appendix 4.
Blood Pressure Control
In type 1 diabetics, blood pressure rises with the development of
microalbuminuria. With the onset of overt proteinuria, hypertension is
usually present and worsens as the nephropathy progresses. However in
type 2 diabetics, hypertension may precede the onset of diabetic
nephropathy and is often associated with the metabolic syndrome of
obesity, insulin resistance and hyperlipidaemia.
Recommendation 5 : Target blood pressure
Target blood pressure in diabetics should be less than 130/80mmHg
Grade A
• Tight blood pressure control is the primary goal in the management of
hypertension in diabetics. This may be achieved with any
antihypertensive agent.
• Hypertension aggravates microvascular and macrovascular
complications of diabetes including diabetic nephropathy.(13)
• Diabetics benefit more from aggressive blood pressure lowering
compared to non-diabetics in the reduction of cardiovascular events.(14-16)
• Tight blood pressure control is also important to slow the progression
of nephropathy and deterioration of renal function.(17,18)
• Target blood pressure should be less than 130/80mmHg if this can be
safely achieved. Although the target is relatively arbitrary, the
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DIABETIC NEPHROPATHY
Hypertension Optimal Treatment (HOT) study has demonstrated the
value of aiming for a diastolic pressure of less than 80mmHg to
reduce cardiovascular and other diabetic complications.(14) However
this can be difficult to achieve and multiple (2 or more) drugs may
be necessary.(19)
• The choice of antihypertensive agent(s) should be individualised,
tailored to patients’ co-morbidities. Diuretics, beta-blockers, calcium
channel blockers, ACEIs or ARBs may be used to achieve the target
blood pressure.
• ACEIs or ARBs may be considered as first line therapy for treatment
of hypertension in diabetics in the absence of contraindications.
Several studies have suggested that ACEIs(20-24) and ARBs(25) may
confer cardioprotective benefits beyond their blood pressure effect in
diabetics although other studies did not show specific advantages.(26,27)
Microalbuminuria
Recommendation 6 : Treatment of microalbuminuria
ACEIs or ARBs should be initiated for the reduction of
microalbuminuria unless contraindicated
ACEIs in type 1 & type 2 diabetics : Grade A
ARBs in type 2 diabetics : Grade A
Refer to Appendix 5 for dosage of commonly used ACEIs and ARBs
• ACEIs(24) and ARBs have been shown to reduce microalbuminuria in
diabetic patients independent of their effect on blood pressure.
• In type 1 diabetic patients with or without hypertension, ACEIs have
been shown to reduce microalbuminuria.(28-31) In type 2 diabetics,
ACEIs(32-38) and more recently ARBs(39-41) have been shown to reduce
microalbuminuria.
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 DIABETIC NEPHROPATHY
Overt Proteinuria
This is the stage when urine is positive for protein by conventional
dipstick. Treatment at this stage should be aimed at aggressive lowering
of blood pressure and reduction of proteinuria.
Recommendation 7 : Target blood pressure in overt nephropathy
In patients with proteinuria > 1 g/day, target blood pressure should be
lowered to < 125/75mmHg
Grade B
The target is extrapolated from the Modification of Diet in Renal Disease
(MDRD) study where 3% of subjects were diabetics. In the subset of
patients with proteinuria of more than 1 g/day, lowering of blood pressure
to below 125/75mmHg was associated with reduction in deterioration of
renal function.(17)
Recommendation 8 : Treatment of overt proteinuria
(a) In Type 1 diabetics with overt proteinuria, ACEIs should be
initiated unless contraindicated
Grade A
(b) In Type 2 diabetics with overt proteinuria, ARBs or ACEIs should
be initiated unless contraindicated
ARBs : Grade A
ACEIs : Grade B
Refer to Appendix 5 for dosage of commonly used ACEIs and ARBs.
• Early studies on type 1 diabetic nephropathy have demonstrated the
effectiveness of blood pressure control with conventional
antihypertensive agents in reducing proteinuria and deterioration of
renal function. (18)
• The most compelling evidence supporting drug specific advantages
beyond blood pressure control has been with ACEIs and ARBs.
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DIABETIC NEPHROPATHY
Landmark studies of ACEIs in type 1(42) and ARBs in type 2
diabetics(43,44) have shown the effectiveness of these agents to retard the
progression of overt diabetic nephropathy. In these trials, there were
significant reductions in the risk of doubling of plasma creatinine and
developing renal failure. These benefits were independent of blood
pressure lowering.
• The role of ACEIs in type 2 diabetics with overt nephropathy is less
clear. As yet, large long-term studies on hard renal endpoints have not
been performed. Small scale studies have shown beneficial effect on
proteinuria but data on retardation of progression of renal failure is
limited.(36,45-49) Despite the lack of direct evidence, an ACEI is a
reasonable alternative to an ARB as it is cheaper and more widely
available.
• Current data suggests that ACEI/ARB should be instituted even in
patients with moderately severe renal failure.(43,44) However renal
function should be monitored closely. Refer to Appendix 5.
• Several small studies have indicated that the combination of ACEI and
ARB may have additive effect in lowering blood pressure and
proteinuria in diabetic patients with microalbuminuria(50,51) and overt
nephropathy.(52,53) Data on long term renoprotective benefits is required.
• Calcium channel blockers (CCBs) have class specific effect on
proteinuria. Non-dihydropyridine CCBs (e.g. verapamil, diltiazem)
have consistently been shown to reduce proteinuria but
dihydropyridine CCBs (e.g. nifedipine, amlodipine) have variable
effect.(54-57)
• There is currently insufficient evidence to support a specific
recommendation on the use of sulodexide, a glycosaminoglycan, in
the treatment of diabetic nephropathy. Small scale studies with short-
term follow-up have suggested that sulodexide may be useful to
reduce urinary albumin excretion rate in type 1 and type 2 diabetics
with microalbuminuria or overt proteinuria.(58,59) The data on its effect
on renal function is limited.
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 DIABETIC NEPHROPATHY
Smoking
Recommendation 9 : Cessation of smoking
Cigarette smoking should be actively discouraged
Grade B
There is clear epidemiological evidence to link smoking to increased risk
of cardiovascular events. Smoking has also been shown to accelerate
progression of diabetic and non-diabetic renal disease and cessation of
smoking ameliorates the decline of renal function.(60-62) Thus patients with
diabetic nephropathy should be strongly advised against smoking.
Lipids
• Diabetics often have abnormal lipid profiles with raised serum
triglycerides, cholesterol and decreased HDL cholesterol level.
• While dyslipidaemia may aggravate renal disease,(63) the evidence
that correction of lipid abnormality slows progression of renal failure
is still lacking. (64-68)
Recommendation 10 : Monitoring of serum lipids
Full lipid profile should be performed at least annually in adult diabetics
Grade C
• Lipid profile should be performed at least annually. However more
frequent monitoring may be required particularly after commencement
of treatment to achieve target levels. (69)
• In diabetic children lipid monitoring every 5 years may be
sufficient.(69)
• In type 1 diabetics, tight glycaemic control is associated with normal
lipoprotein level. Thus, good glycaemic control in type 1 diabetics may
be more important than in type 2 diabetics to reduce cardiovascular
risk.(70)
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DIABETIC NEPHROPATHY
Recommendation 11 : Correction of dyslipidaemia
In diabetics :
(a) therapeutic lifestyle changes should be instituted if LDL-
cholesterol is > 2.6 mmol/l
(b) drug therapy should be considered if LDL-cholesterol is > 3.4
mmol/l
Grade B*
* recommendations are graded on evidence from trials on diabetics in general as data in
diabetic nephropathy is limited
• Dyslipidaemia in diabetics should be identified and aggressively
treated.
• All diabetics should be encouraged to go on a therapeutic lifestyle
change comprising increased physical activity, reduction in intake of
saturated fat and cholesterol, as well as achievement of ideal body
weight.(69)
• Therapy with lipid lowering drugs, especially with statins, has been
shown to reduce cardiovascular morbidity and mortality in diabetics
and in other patients at high risk of clinical atherosclerotic disease.(70-72)
• There have been no large randomised placebo-controlled trials to show
the effects of lipid lowering in patients with diabetic nephropathy.
Nevertheless the beneficial outcome of lipid lowering in the diabetic
population in general supports aggressive on-going therapy when
nephropathy develops.
• In diabetics with LDL-cholesterol above 3.4 mmol/l, drug therapy
should be considered to achieve an ideal LDL-cholesterol level of
under 2.6 mmol/l (or to achieve non- HDL-cholesterol of under 3.4
mmol/l). Statins are drugs of first choice, with fibrates as an alternative
especially in those with low HDL-cholesterol and high
triglycerides.(73,74)
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 DIABETIC NEPHROPATHY
• As patients with renal failure are at a higher risk of myositis with lipid
lowering drugs lower doses should be used when commencing therapy
and increased cautiously. Combination of statins and fibrates should be
avoided in renal failure. Refer to Appendix 4.
Diet
Recommendation 12 : Protein restriction
Moderate protein restriction of 0.6 – 0.8 g/kg/day* may be considered
in patients with overt nephropathy and/or renal impairment
Grade B
* one matchbox sized cooked protein source is equivalent to 7g of protein
• With the onset of overt nephropathy, protein restriction of
0.8g/kg/body weight or less may be useful in slowing the decline of
GFR.(75-78) More severe protein restriction of < 0.6g/kg/body weight
may further retard the progression of diabetic nephropathy. However,
this should be supervised by an experienced dietitian to prevent
malnutrition.(79)
Recommendation 13 : Sodium restriction
Sodium intake should be restricted to < 80mmol/day (or 5g sodium
chloride)* in patients with hypertension and/or proteinuria
Grade B
* equivalent to 1 teaspoon of salt
• High sodium intake should be avoided.
• Moderate sodium restriction can potentiate the hypotensive effect of
many antihypertensives.(80-83)
• A low sodium diet enhances the antiproteinuric effects of some
antihypertensives e.g. ARBs, ACEIs.(84,85)
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DIABETIC NEPHROPATHY
Referral
Recommendation 14 : Referral to nephrologist
Referral to a nephrologist should be made if the serum creatinine
exceeds 200 umol/L
Grade C
• Several studies have shown that late referral leads to increased
morbidity, prolonged hospital stay and early mortality on dialysis.(86-94)
Uraemic symptoms and complications often occur earlier in diabetics
compared to non-diabetics and dialysis may be required once GFR
falls to 10 to 15mls/min.(95-97)
• Pre-dialysis evaluation should be considered once the serum creatinine
exceeds 200 umol/l. Measures that would need to be instituted include :-
- optimisation of blood pressure control and proteinuria reduction to
retard further progression of renal failure
- correction of anaemia
- correction of calcium and phosphate abnormalities
- nutritional management
- counselling and assessment for dialysis
- early preparation of access for dialysis
• Earlier referral to a nephrologist may be indicated if :-
- the diagnosis of diabetic nephropathy is in doubt e.g. proteinuria
occurs in the absence of retinopathy, renal failure occurs without
proteinuria
- nephrotic syndrome or unexplained haematuria occurs
- a sudden worsening of renal function occurs
- blood pressure is difficult to control
- hyperkalaemia arises
- renal artery stenosis is suspected
• Diabetic patients on renal replacement therapy (i.e. dialysis or
transplant) have a 2 to 4 times higher mortality risk than non-diabetic
patients, mainly from cardiovascular disease. Coronary artery
revascularisation may reduce this complication especially in type 1
diabetics.(98,99)
17

Factors affecting urinary albumin excretion (100,101)
Increases AER
• Strenuous exercise
• Poorly controlled diabetes
mellitus
• Heart failure
• Urinary tract infection
• Acute febrile illness
• Uncontrolled hypertension
• Haematuria
• Menstruation
• Pregnancy
AER = Albumin excretion rate
DIABETIC NEPHROPATHY DIABETIC NEPHROPATHY
Appendix 1 Appendix 2
Methods of urine collection
24-hour urine collection
Decreases AER
• NSAIDs • 24-hour urine collection minimises fluctuations in urinary albumin
• ACE inhibitors excretion (UAE) due to diurnal variation.
• Patients should receive clear instructions on how to collect the urine
sample to avoid incomplete collection.
• Patients should be instructed to pass urine completely at a specified
time. The first urine voided is NOT collected.
• Subsequently ALL urine passed should be collected into a urine bottle
until the next day when the last sample of urine is collected at precisely
the same time as the first voided urine.

• Patients should be instructed to void completely at first and last void

particularly in patients with incomplete evacuation of the bladder e.g.
patients with diabetic cystopathy, prostatic hypertrophy or other
bladder outlet obstruction.

Timed overnight urine collection

• Patients should be instructed to pass urine completely before retiring to

bed and to record the exact time. The urine voided is NOT collected.

• Subsequently any urine passed during the night should be collected

into a bottle.

• Upon waking the next morning, the patient should pass urine
completely into the bottle. The exact time of this collection should be
recorded.

18 19
 DIABETIC NEPHROPATHY DIABETIC NEPHROPATHY
Appendix 2 Appendix 3
Methods of measurement of microalbuminuria
• The urine should be sent to the laboratory for quantification of urinary
Methods Tests Sensiti- Specifi- Advantages Disadvantages
albumin on the same day.
vity city
24h urine 1. Radio- Quantitative, Expensive,
• UAE (µg/min) = urine albumin concentration (µg/l) x urine volume (l) albumin immunoassay can also inconvenient,
duration of urine collection (min) measurement measure impractical,
2. ELISA creatinine incomplete
clearance collection
Early morning spot urine 3.Immuno- simultaneously common
nephelometric
Timed method e. g. Quantitative, Expensive
• An early morning urine sample is more reliable than a random sample. overnight Assay® analyser not affected by
The urine of an early morning sample is more concentrated and less urine
(from Beckman) physical
liable to be affected by fluid intake during daytime. Early morning albumin
activity
collection also minimises variation in albumin excretion rate due to measurement
changes in posture and physical activity. Clinitek 50® 89% 91% Cheap, simple,
Urine
albumin: Microalbumin corrects for
• Patients should be instructed to pass urine before retiring to bed. creatinine Reagent Strip changes in
ratio for ACR urine
• The next morning, the first urine voided should be collected and (ACR)* concentration
brought to the clinic for testing as early as possible.
DCA2000 91.1% 98.3% Immediate Expensive
Microalbumin/ (7 mins),
creatinine quantitative
Assay System determination

Urine Micral Test II® 96.7% 71% Cheap, simple, Semi-

albumin (Co.) reliable, rapid quantitative
concentra- on-site test Subject to
tion* errors from
alteration in
urine
Clinitek 50 92% 93% concentration
Albumin test
pad (Co.)

* dipstick test on spot urine sample for detection of urine microalbumin

20 21
 DIABETIC NEPHROPATHY DIABETIC NEPHROPATHY
Appendix 4 Appendix 4
Dosage of hypoglycaemic agents in renal failure • Gliclazide, glipizide and glimepiride (completely metabolised to
Dose adjustment in renal failure* inactive products) are safer alternatives. Lower starting doses should
Generic name Usual dose Mild Moderate Severe be used.
(GFR 60- (GFR 30- (GFR <
90ml/min) 60ml/min) 30ml/min) Meglitinides
Sulphonylureas • Repaglinide and nateglinide have short half-lives and duration of
Glibenclamide 5mg od - 10mg bd 25-50% Avoid Avoid action with lower risk of hypoglycaemia.
Gliclazide 80mg od - 160mg bd 50-100% 25-50% Avoid
Glipizide 2.5mg od - 15mg od 100% 50% Avoid Thiazolidinediones
Chlorpropamide 250mg od - 500mg od Avoid Avoid Avoid
• Rosiglitazone can be used in mild to moderate renal failure but can
Glimepiride 1mg od - 4mg od 100% 50% Avoid
cause fluid retention.
Others
Insulin Variable 100% 75% 50%
Metformin 500mg bd - 1g bd 50% 25% Avoid
Rosiglitazone 4 - 8mg od 100% 100% 50-100%
Acarbose 25mg tds - 100mg tds 50-100% 50-100% Avoid
Repaglinide 0.5mg tds - 4mg tds 100% 100% 50-100%
Nateglinide 120mg tds 100% 100% 50-100%
od = once daily, bd = twice daily, tds = three times daily
*Refer to Appendix 6 for Cockcroft-Gault formula to estimate renal function

Insulin
• In renal failure the dose of insulin should be reduced to avoid
hypoglycaemia as insulin is degraded by the kidney.
• Conversion to short acting insulin may be required.

Biguanides
• Metformin should be avoided if the serum creatinine is above 150 -
200umol/L as it can rarely cause lactic acidosis in renal failure.

Sulphonylureas
• Chlorpropamide is contraindicated in renal failure as it has a long half-
life and its metabolites retain some hypoglycaemic effects.
• Glibenclamide should be avoided in renal failure as it has a long
biologic effect despite its short plasma half-life.

22 23
 DIABETIC NEPHROPATHY DIABETIC NEPHROPATHY
Appendix 5 Appendix 6
Dosage of commonly used ACEIs and ARBs Estimation of renal function
ACEI Starting dose Maximum dose
Captopril 6.25mg tds 50mg tds Cockcroft-Gault formula(103)
Enalapril 2.5mg bd 20mg bd
Ramipril 2.5mg od 10mg od Creatinine clearance (ml/min)= (140 – age) x weight x 0.85 (for females)
Lisinopril 5mg od 40mg od 0.814 x plasma creatinine
Perindopril 2mg od 8mg od
Fosinopril 10mg od 40mg od Age in years, Weight in kg, Creatinine in umol/l
Quinapril 5mg od 40mg od

ARB Starting dose Maximum dose

Losartan 50mg od 100mg od
Irbesartan 150mg od 300mg od
Valsartan 80mg od 160mg bd
Candesartan 8mg od 16mg bd
Telmisartan 40mg od 80mg od
od = once daily, bd = twice daily, tds = three times daily

• ACEIs/ARBs should be used with caution in patients with bilateral

renal artery stenosis or renal artery stenosis of a single functioning
kidney.
• ACEIs/ARBs should be started at lower doses in renal failure and
titrated gradually to maximal tolerable dose to achieve anti-proteinuric
effect.
• Serum potassium and creatinine should be checked prior to and within
one to two weeks after initiating an ACEI or ARB as they can
occasionally cause worsening of renal function.
• If serum creatinine increases acutely by more than 35%(102) or severe
hyperkalaemia occurs, the drug may need to be reduced or withdrawn.
Renal artery stenosis may need to be excluded.
• Diuretics may potentiate the hypotensive and anti-proteinuric effect of
ACEIs/ARBs.
• Potassium sparing diuretics may worsen hyperkalaemia when
combined with ACEI/ARB in the presence of renal failure. Careful
monitoring of serum potassium is advisable.

24 25
 DIABETIC NEPHROPATHY
REFERENCES
1. Scottish Intercollegiate Guidelines Network. SIGN 11: Management
of diabetic renal disease – a National Clinical Guideline
recommended for use in Scotland. March 1997
2. Lim TO, Lim YN. Ninth report of the Malaysian Dialysis and
Transplant Registry 2002
3. Public Health Institute (Ministry of Health). Malaysian National
Health and Morbidity Survey 2. 1996-1997
4. Breyer JA. Diabetic nephropathy in insulin-dependent patients. Am
J Kidney Dis 1992;20(6):533-47
5. The Diabetes Control and Complications Trial Research Group.
The effect of intensive treatment of diabetes on the development
and progression of long-term complications in insulin-dependent
diabetes mellitus. N Engl J Med 1993;329(14):977-86
6. The Diabetes Control and Complications Trial/Epidemiology of
Diabetes Interventions and Complications Research Group.
Retinopathy and nephropathy in patients with type 1 diabetes four
years after a trial of intensive therapy. N Engl J Med
2000;342(6):381-9
7. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-
glucose control with sulphonylureas or insulin compared with
conventional treatment and risk of complications in patients with
type 2 diabetes (UKPDS 33). Lancet 1998;352(9131):837-53
8. Mogensen CE, Viberti GC, Peheim E, Kutter D, Hasslacher C,
Hofmann W, Renner R, Bojestig M, Poulsen PL, Scott G, Thoma J,
Kuefer J, Nilsson B, Gambke B, Mueller P, Steinbiss J,
Willamowski KD. Multicenter evaluation of the Micral-Test II test
strip, an immunologic rapid test for the detection of
microalbuminuria. Diabetes Care 1997;20(11):1642-6
9. Messent JW, Elliott TG, Hill RD, Jarrett RJ, Keen H, Viberti GC.
Prognostic significance of microalbuminuria in insulin-dependent
diabetes mellitus: a twenty-three year follow-up study. Kidney Int
1992;41(4):836-9
26
DIABETIC NEPHROPATHY
10. Mattock MB, Morrish NJ, Viberti G, Keen H, Fitzgerald AP,
Jackson G. Prospective study of microalbuminuria as predictor of
mortality in NIDDM. Diabetes 1992;41(6):736-41
11. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive
blood-glucose control with metformin on complications in
overweight patients with type 2 diabetes (UKPDS 34). Lancet
1998;352(9131):854-65
12. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA,
Hadden D, Turner RC, Holman RR. Association of glycaemia with
macrovascular and microvascular complications of type 2 diabetes
(UKPDS 35): prospective observational study. BMJ
2000;321(7258):405-12
13. Adler AI, Stratton IM, Neil HA, Yudkin JS, Matthews DR, Cull CA,
Wright AD, Turner RC, Holman RR. Association of systolic blood
pressure with macrovascular and microvascular complications of
type 2 diabetes (UKPDS 36): prospective observational study. BMJ
2000;321(7258):412-9
14. Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius
S, Menard J, Rahn KH, Wedel H, Westerling S for the HOT Study
Group. Effects of intensive blood-pressure lowering and low-dose
aspirin in patients with hypertension: principal results of the
Hypertension Optimal Treatment (HOT) randomised trial. Lancet
1998;351(9118):1755-62
15. Tuomilehto J, Rastenyte D, Birkenhager WH, Thijs L, Antikainen R,
Bulpitt CJ, Fletcher AE, Forette F, Goldhaber A, Palatini P, Sarti C,
Fagard R for the Systolic Hypertension in Europe Trial Investigators.
Effects of calcium-channel blockade in older patients with diabetes
and systolic hypertension. N Engl J Med 1999;340(9):677-84
16. Curb JD, Pressel SL, Cutler JA, Savage PJ, Applegate WB, Black H,
Camel G, Davis BR, Frost PH, Gonzalez N, Guthrie G, Oberman A,
Rutan GH, Stamler J for the Systolic Hypertension in the Elderly
Program Cooperative Research Group. Effect of diuretic-based
antihypertensive treatment on cardiovascular disease risk in older
diabetic patients with isolated systolic hypertension. JAMA
1996;276(23):1886-92
27
 DIABETIC NEPHROPATHY
17. Peterson JC, Adler S, Burkart JM, Greene T, Hebert LA, Hunsicker
LG, King AJ, Klahr S, Massry SG, Seifter JL. Blood pressure
control, proteinuria, and the progression of renal disease. The
Modification of Diet in Renal Disease Study. Ann Intern Med
1995;123(10):754-62
18. Breyer JA. Therapeutic interventions for nephropathy in type I
diabetes mellitus. Semin Nephrol 1997;17(2):114-23
19. Bakris GL, Williams M, Dworkin L, Elliott WJ, Epstein M, Toto R,
Tuttle K, Douglas J, Hsueh W, Sowers J for National Kidney
Foundation Hypertension and Diabetes Executive Committees
Working Group. Preserving renal function in adults with
hypertension and diabetes: a consensus approach. Am J Kidney Dis
2000;36(3):646-61
20. Pahor M, Psaty BM, Alderman MH, Applegate WB, Williamson JD,
Furberg CD. Therapeutic benefits of ACE inhibitors and other
antihypertensive drugs in patients with type 2 diabetes. Diabetes
Care 2000;23(7):888-92
21. Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N,
Schrier RW. The effect of nisoldipine as compared with enalapril on
cardiovascular outcomes in patients with non-insulin-dependent
diabetes and hypertension. N Engl J Med 1998;338(10):645-52
22. Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, Niklason
A, Luomanmaki K, Dahlof B, de Faire U, Morlin C, Karlberg BE,
Wester PO, Bjorck JE. Effect of angiotensin-converting-enzyme
inhibition compared with conventional therapy on cardiovascular
morbidity and mortality in hypertension: the Captopril Prevention
Project (CAPPP) randomised trial. Lancet 1999;353(9153):611-6
23. Tatti P, Pahor M, Byington RP, Di Mauro P, Guarisco R, Strollo G,
Strollo F. Outcome results of the Fosinopril Versus Amlodipine
Cardiovascular Events Randomized Trial (FACET) in patients with
hypertension and NIDDM. Diabetes Care 1998;21(4):597-603
24. Heart Outcomes Prevention Evaluation Study Investigators. Effects
of ramipril on cardiovascular and microvascular outcomes in people
with diabetes mellitus: results of the HOPE study and MICRO-
HOPE substudy. Lancet 2000;355(9200):253-9
28
DIABETIC NEPHROPATHY
25. Lindholm LH, Ibsen H, Dahlof B, Devereux RB, Beevers G, de Faire
U, Fyhrquist F, Julius S, Kjeldsen SE, Kristiansson K, Lederballe-
Pedersen O, Nieminen MS, Omvik P, Oparil S, Wedel H, Aurup P,
Edelman J, Snapinn S; The LIFE Study Group. Cardiovascular
morbidity and mortality in patients with diabetes in the Losartan
Intervention For Endpoint reduction in hypertension study (LIFE): a
randomised trial against atenolol. Lancet 2002;359(9311):1004-10
26. UK Prospective Diabetes Study Group. Efficacy of atenolol and
captopril in reducing risk of macrovascular and microvascular
complications in type 2 diabetes: UKPDS 39. BMJ
1998;317(7160):713-20
27. The ALLHAT Collaborative Research Group. Major outcomes in
high-risk hypertensive patients randomized to angiotensin-
converting enzyme inhibitor or calcium channel blocker vs diuretic:
The Antihypertensive and Lipid-Lowering Treatment to Prevent
Heart Attack Trial (ALLHAT). JAMA 2002;288(23):2981-97
28. Mathiesen ER, Hommel E, Giese J, Parving HH. Efficacy of
captopril in postponing nephropathy in normotensive insulin
dependent diabetic patients with microalbuminuria. BMJ
1991;303(6794):81-7
29. Laffel LM, McGill JB, Gans DJ for the North American
Microalbuminuria Study Group. The beneficial effect of angiotensin-
converting enzyme inhibition with captopril on diabetic nephropathy
in normotensive IDDM patients with microalbuminuria. Am J Med
1995;99(5):497-504
30. The Microalbuminuria Captopril Study Group. Captopril reduces the
risk of nephropathy in IDDM patients with microalbuminuria.
Diabetologia 1996;39(5):587-93
31. The EUCLID Study Group. Randomised placebo-controlled trial of
lisinopril in normotensive patients with insulin-dependent diabetes
and normoalbuminuria or microalbuminuria. Lancet 1997;349
(9068):1787-92
32. Ravid M, Savin H, Jutrin I, Bental T, Katz B, Lishner M. Long-term
stabilizing effect of angiotensin-converting enzyme inhibition on
plasma creatinine and on proteinuria in normotensive type II diabetic
patients. Ann Intern Med 1993;118(8):577-81
29
 DIABETIC NEPHROPATHY
33. Ravid M, Lang R, Rachmani R, Lishner M. Long-term
renoprotective effect of angiotensin-converting enzyme inhibition in
non-insulin-dependent diabetes mellitus. A 7-year follow-up study.
Arch Intern Med 1996;156(3):286-9
34. Sano T, Hotta N, Kawamura T, Matsumae H, Chaya S, Sasaki H,
Nakayama M, Hara T, Matsuo S, Sakamoto N. Effects of long-term
enalapril treatment on persistent microalbuminuria in normotensive
type 2 diabetic patients: results of a 4-year, prospective, randomized
study. Diabet Med 1996;13(2):120-4
35. Lacourciere Y, Nadeau A, Poirier L, Tancrede G. Captopril or
conventional therapy in hypertensive type II diabetics. Three-year
analysis. Hypertension 1993;21(6 Pt 1):786-94
36. Lebovitz HE, Wiegmann TB, Cnaan A, Shahinfar S, Sica DA,
Broadstone V, Schwartz SL, Mengel MC, Segal R, Versaggi JA, et
al. Renal protective effects of enalapril in hypertensive NIDDM: role
of baseline albuminuria. Kidney Int Suppl 1994;45:S150-5
37. Mosconi L, Ruggenenti P, Perna A, Mecca G, Remuzzi G.
Nitrendipine and enalapril improve albuminuria and glomerular
filtration rate in non-insulin dependent diabetes. Kidney Int Suppl
1996;55:S91-3
38. Velussi M, Brocco E, Frigato F, Zolli M, Muollo B, Maioli M,
Carraro A, Tonolo G, Fresu P, Cernigoi AM, Fioretto P, Nosadini R.
Effects of cilazapril and amlodipine on kidney function in
hypertensive NIDDM patients. Diabetes 1996;45(2):216-22
39. Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen
S, Arner P. The effect of irbesartan on the development of diabetic
nephropathy in patients with type 2 diabetes. N Engl J Med
2001;345(12):870-8
40. Lozano JV, Llisterri JL, Aznar J, Redon J. Losartan reduces
microalbuminuria in hypertensive microalbuminuric type 2
diabetics. Nephrol Dial Transplant 2001;16 Suppl 1:85-9
41. Viberti G, Wheeldon NM; MicroAlbuminuria Reduction With
VALsartan (MARVAL) Study Investigators. Microalbuminuria
reduction with valsartan in patients with type 2 diabetes mellitus: a
blood pressure-independent effect. Circulation 2002;106(6):672-8
30
DIABETIC NEPHROPATHY
42. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD for The Collaborative
Study Group. The effect of angiotensin-converting-enzyme
inhibition on diabetic nephropathy. N Engl J Med
1993;329(20):1456-62
43. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE,
Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S for the
RENAAL Study Investigators. Effects of losartan on renal and
cardiovascular outcomes in patients with type 2 diabetes and
nephropathy. N Engl J Med 2001;345(12):861-9
44. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB,
Ritz E, Atkins RC, Rohde R, Raz I for the Collaborative Study
Group. Renoprotective effect of the angiotensin-receptor antagonist
irbesartan in patients with nephropathy due to type 2 diabetes. N
Engl J Med 2001;345(12):851-60
45. Estacio RO, Jeffers BW, Gifford N, Schrier RW. Effect of blood
pressure control on diabetic microvascular complications in patients
with hypertension and type 2 diabetes. Diabetes Care 2000;23 Suppl
2:B54-64
46. Bakris GL, Copley JB, Vicknair N, Sadler R, Leurgans S. Calcium
channel blockers versus other antihypertensive therapies on
progression of NIDDM associated nephropathy. Kidney Int
1996;50(5):1641-50
47. Fogari R, Zoppi A, Corradi L, Mugellini A, Lazzari P, Preti P,
Lusardi P. Long-term effects of ramipril and nitrendipine on
albuminuria in hypertensive patients with type II diabetes and
impaired renal function. J Hum Hypertens 1999;13(1):47-53
48. Nielsen FS, Rossing P, Gall MA, Skott P, Smidt UM, Parving HH.
Long-term effect of lisinopril and atenolol on kidney function in
hypertensive NIDDM subjects with diabetic nephropathy. Diabetes
1997;46(7):1182-8
49. Walker WG, Hermann J, Anderson J, et al. Blood pressure (BP)
control slows decline of glomerular filtration rate (GFR) in
hypertensive NIDDM patients [abstract]. J Am Soc Nephrol 1992,
3:339
31
 DIABETIC NEPHROPATHY
50. Mogensen CE, Neldam S, Tikkanen I, Oren S, Viskoper R, Watts
RW, Cooper ME. Randomised controlled trial of dual blockade of
renin-angiotensin system in patients with hypertension,
microalbuminuria, and non-insulin dependent diabetes: the
candesartan and lisinopril microalbuminuria (CALM) study. BMJ
2000;321(7274):1440-4.
51. Tutuncu NB, Gurlek A, Gedik O. Efficacy of ACE inhibitors and
ATII receptor blockers in patients with microalbuminuria: a
prospective study. Acta Diabetol 2001;38(4):157-61.
52. Rossing K, Christensen PK, Jensen BR, Parving HH. Dual blockade
of the renin-angiotensin system in diabetic nephropathy: a
randomized double-blind crossover study. Diabetes Care
2002;25(1):95-100
53. Jacobsen P, Andersen S, Rossing K, Jensen BR, Parving HH. Dual
blockade of the renin-angiotensin system versus maximal
recommended dose of ACE inhibition in diabetic nephropathy.
Kidney Int. 2003;63(5):1874-80
54. Bohlen L, de Courten M, Weidmann P. Comparative study of the
effect of ACE-inhibitors and other antihypertensive agents on
proteinuria in diabetic patients. Am J Hypertens 1994;7(9 Pt 2):84S-
92S
55. Bakris GL. The effects of calcium antagonists on renal
hemodynamics, urinary protein excretion, and glomerular
morphology in diabetic states. J Am Soc Nephrol 1991;2(2 Suppl
1):S21-9
56. Demarie BK, Bakris GL. Effects of different calcium antagonists on
proteinuria associated with diabetes mellitus. Ann Intern Med
1990;113(12):987-8
57. Guasch A, Parham M, Zayas CF, Campbell O, Nzerue C, Macon E.
Contrasting effects of calcium channel blockade versus converting
enzyme inhibition on proteinuria in African Americans with non-
insulin-dependent diabetes mellitus and nephropathy. J Am Soc
Nephrol 1997;8(5):793-8
32
DIABETIC NEPHROPATHY
58. Gambaro G, Kinalska I, Oksa A, Pont'uch P, Hertlova M, Olsovsky
J, Manitius J, Fedele D, Czekalski S, Perusicova J, Skrha J, Taton J,
Grzeszczak W, Crepaldi G. Oral sulodexide reduces albuminuria in
microalbuminuric and macroalbuminuric type 1 and type 2 diabetic
patients: the Di.N.A.S. randomized trial. J Am Soc Nephrol
2002;13(6):1615-25
59. Dedov I, Shestakova M, Vorontzov A, Palazzini E. A randomized,
controlled study of sulodexide therapy for the treatment of diabetic
nephropathy. Nephrol Dial Transplant 1997;12(11):2295-300
60. Ritz E, Ogata H, Orth SR. Smoking: a factor promoting onset and
progression of diabetic nephropathy. Diabetes Metab 2000;26 Suppl
4:54-63
61. Gambaro G, Bax G, Fusaro M, Normanno M, Manani SM, Zanella
M, Dangelo A, Fedele D, Favaro S. Cigarette smoking is a risk factor
for nephropathy and its progression in type 2 diabetes mellitus.
Diabetes Nutr Metab 2001;14(6):337-42
62. Schiffl H, Lang SM, Fischer R. Stopping smoking slows accelerated
progression of renal failure in primary renal disease. J Nephrol 2002
May-Jun;15(3):270-4
63. Wanner C, Quaschning T. Dyslipidemia and renal disease:
pathogenesis and clinical consequences. Curr Opin Nephrol
Hypertens 2001;10(2):195-201
64. Fried LF, Orchard TJ, Kasiske BL. Effect of lipid reduction on the
progression of renal disease: a meta-analysis. Kidney Int
2001;59(1):260-9
65. Lam KS, Cheng IK, Janus ED, Pang RW. Cholesterol-lowering
therapy may retard the progression of diabetic nephropathy.
Diabetologia 1995 May;38(5):604-9
66. Fried LF, Forrest KY, Ellis D, Chang Y, Silvers N, Orchard TJ. Lipid
modulation in insulin-dependent diabetes mellitus: effect on
microvascular outcomes. J Diabetes Complications 2001;15(3):
113-9
33
 DIABETIC NEPHROPATHY
67. Tonolo G, Ciccarese M, Brizzi P, Puddu L, Secchi G, Calvia P,
Atzeni MM, Melis MG, Maioli M. Reduction of albumin excretion
rate in normotensive microalbuminuric type 2 diabetic patients
during long-term simvastatin treatment. Diabetes Care
1997;20(12):1891-5
68. Smulders YM, van Eeden AE, Stehouwer CD, Weijers RN, Slaats
EH, Silberbusch J. Can reduction in hypertriglyceridaemia slow
progression of microalbuminuria in patients with non-insulin-
dependent diabetes mellitus? Eur J Clin Invest 1997;27(12):997-
1002
69. American Diabetes Association. Standards of medical care for
patients with diabetes mellitus. (Position Statement). Diabetes Care
2003; 26 Suppl 1:S33-50
70. The Long-Term Intervention with Pravastatin in Ischaemic Disease
(LIPID) Study Group. Prevention of cardiovascular events and death
with pravastatin in patients with coronary heart disease and a broad
range of initial cholesterol levels. N Engl J Med 1998;339(19):1349-
57
71. Heart Protection Study Collaborative Group. MRC/BHF Heart
Protection Study of cholesterol lowering with simvastatin in 20,536
high-risk individuals: a randomised placebo-controlled trial. Lancet
2002;360(9326):7-22
72. Haffner SM, Alexander CM, Cook TJ, Boccuzzi SJ, Musliner TA,
Pedersen TR, Kjekshus J, Pyorala K. Reduced coronary events in
simvastatin-treated patients with coronary heart disease and diabetes
or impaired fasting glucose levels: subgroup analyses in the
Scandinavian Simvastatin Survival Study. Arch Intern Med
1999;159(22):2661-7
73. American Diabetes Association. Management of dyslipidemia in
adults with diabetes (Position Statement). Diabetes Care 2003;26
Suppl 1:S83-6
74. Executive Summary of The Third Report of The National
Cholesterol Education Program (NCEP) Expert Panel on Detection,
Evaluation, And Treatment of High Blood Cholesterol In Adults
(Adult Treatment Panel III). JAMA 2001;285(19):2486-97
34
DIABETIC NEPHROPATHY
75. Walker JD, Bending JJ, Dodds RA, Mattock MB, Murrells TJ, Keen
H, Viberti GC. Restriction of dietary protein and progression of renal
failure in diabetic nephropathy. Lancet 1989;2(8677):1411-5
76. Zeller K, Whittaker E, Sullivan L, Raskin P, Jacobson HR. Effect of
restricting dietary protein on the progression of renal failure in
patients with insulin-dependent diabetes mellitus. N Engl J Med
1991;324(2):78-84
77. Ciavarella A, Di Mizio G, Stefoni S, Borgnino LC, Vannini P.
Reduced albuminuria after dietary protein restriction in insulin-
dependent diabetic patients with clinical nephropathy. Diabetes Care
1987;10(4):407-13
78. Pedrini MT, Levey AS, Lau J, Chalmers TC, Wang PH. The effect of
dietary protein restriction on the progression of diabetic and
nondiabetic renal diseases: a meta-analysis. Ann Intern Med
1996;124(7):627-32
79. American Diabetes Association. Diabetic nephropathy (Position
Statement). Diabetes Care 2003;26 Suppl 1:S94-8
80. Australian National Health & Medical Research Council Dietary Salt
Study Management Committee. Effects of replacing sodium intake
in subjects on a low sodium diet: a crossover study. Clin Exp
Hypertens A 1989;11(5-6):1011-24
81. Weir MR, Dworkin LD. Antihypertensive drugs, dietary salt, and
renal protection: how low should you go and with which therapy?
Am J Kidney Dis 1998;32(1):1-22
82. MacGregor GA, Markandu ND, Singer DR, Cappuccio FP, Shore
AC, Sagnella GA. Moderate sodium restriction with angiotensin
converting enzyme inhibitor in essential hypertension: a double blind
study. Br Med J 1987;294(6571):531-4
83. The Royal College of General Practitioners. Clinical guidelines for
type 2 diabetes – Diabetic renal disease: prevention and early
management. March 2002
84. Houlihan CA, Allen TJ, Baxter AL, Panangiotopoulos S, Casley DJ,
Cooper ME, Jerums G. A low-sodium diet potentiates the effects of
losartan in type 2 diabetes. Diabetes Care 2002;25(4):663-71
85. Heeg JE, de Jong PE, van der Hem GK, de Zeeuw D. Efficacy and
variability of the antiproteinuric effect of ACE inhibition by
lisinopril. Kidney Int 1989;36(2):272-9
35
 DIABETIC NEPHROPATHY
86. Obrador GT, Pereira BJ. Early referral to the nephrologist and timely
initiation of renal replacement therapy: a paradigm shift in the
management of patients with chronic renal failure. Am J Kidney Dis
1998;31(3):398-417
87. Arora P, Obrador GT, Ruthazer R, Kausz AT, Meyer KB, Jenuleson
CS, Pereira BJ. Prevalence, predictors, and consequences of late
nephrology referral at a tertiary care center. J Am Soc Nephrol
1999;10(6):1281-6
88. Ifudu O, Dawood M, Homel P, Friedman EA. Excess morbidity in
patients starting uremia therapy without prior care by a nephrologist.
Am J Kidney Dis 1996;28(6):841-5
89. Sesso R, Belasco AG. Late diagnosis of chronic renal failure and
mortality on maintenance dialysis. Nephrol Dial Transplant
1996;11(12):2417-20
90. Innes A, Rowe PA, Burden RP, Morgan AG. Early deaths on renal
replacement therapy: the need for early nephrological referral.
Nephrol Dial Transplant 1992;7(6):467-71
91. Jungers P, Zingraff J, Albouze G, Chauveau P, Page B, Hannedouche
T, Man NK. Late referral to maintenance dialysis: detrimental
consequences. Nephrol Dial Transplant 1993;8(10):1089-93
92. Ratcliffe PJ, Phillips RE, Oliver DO. Late referral for maintenance
dialysis. BMJ 1984;288(6415):441-3
93. Stack AG. Impact of timing of nephrology referral and pre-ESRD
care on mortality risk among new ESRD patients in the United
States. Am J Kidney Dis 2003;41(2):310-8
94. Astor BC, Eustace JA, Powe NR, Klag MJ, Sadler JH, Fink NE,
Coresh J. Timing of nephrologist referral and arteriovenous access
use: the CHOICE Study. Am J Kidney Dis 2001;38(3):494-501
95. Becker BN, Stone WJ. Options for renal replacement therapy:
special considerations. Semin Nephrol 1997;17(3):176-87
96. Khanna R. Dialysis considerations for diabetic patients. Kidney Int
Suppl 1993;40:S58-64
97. Pirson Y. The diabetic patient with ESRD: how to select the modality
of renal replacement. Nephrol Dial Transplant 1996;11(8):1511-3
36
DIABETIC NEPHROPATHY
98. Manske CL, Wang Y, Rector T, Wilson RF, White CW. Coronary
revascularisation in insulin-dependent diabetic patients with chronic
renal failure. Lancet 1992;340(8826):998-1002
99. Brunner FP, Selwood NH. Profile of patients on RRT in Europe and
death rates due to major causes of death groups. The EDTA
Registration Committee. Kidney Int Suppl 1992;38:S4-15
100. Phillipou G, Phillips PJ. Variability of urinary albumin excretion in
patients with microalbuminuria. Diabetes Care 1994;17(5):425-7
101. Mogensen CE, Vestbo E, Poulsen PL, Christiansen C, Damsgaard
EM, Eiskjaer H, Froland A, Hansen KW, Nielsen S, Pedersen MM.
Microalbuminuria and potential confounders. A review and some
observations on variability of urinary albumin excretion. Diabetes
Care 1995;18(4):572-81
102. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo
JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ;
National Heart, Lung, and Blood Institute Joint National Committee
on Prevention, Detection, Evaluation, and Treatment of High Blood
Pressure; National High Blood Pressure Education Program
Coordinating Committee. The Seventh Report of the Joint National
Committee on Prevention, Detection, Evaluation, and Treatment of
High Blood Pressure: the JNC 7 report. JAMA 2003;289(19):2560-
72
103. Cockcroft DW, Gault MH. Prediction of creatinine clearance from
serum creatinine. Nephron 1976;16(1):31-41
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GLOSSARY OF TERMS

ACEI Angiotensin converting enzyme inhibitor

ACR Albumin creatinine ratio
AER Albumin excretion rate
ARB Angiotensin receptor blocker
BP Blood pressure
CCB Calcium channel blocker
CCF Congestive cardiac failure
ESRD End stage renal disease
GFR Glomerular filtration rate
HDL High density lipoprotein
LDL Low density lipoprotein
NSAID Non-steroidal anti-inflammatory drug
RCT Randomised controlled trial
UTI Urinary tract infection

DISCLOSURE STATEMENT

The panel members have no potential conflict of interest to disclose.

ACKNOWLEDGEMENTS

The panel would like to thank the following persons/organisations for their
assistance during the preparation of this guideline :

• Ms Lim Chi Lin, Ms Chan Cheah Eing and Mr. Nicholas Sean Surin, for
their secretarial services

• Prof. Dick de Zeeuw, Professor and Head of Clinical Pharmacology at

the University of Groningen, The Netherlands and Prof. Hugh R. Brady,
Professor of Medicine and Therapeutics at University College Dublin,
Ireland for their helpful suggestions

• Puan Zubaidah bt Che Embee, Pharmacist, Penang Hospital for her

assistance with the drug dosing tables
38